The present invention relates to pharmaceutical formulations comprising stabilized polysaccharides and a source of hydrogen peroxide. In particular, the present invention relates to such formulations that are used in ophthalmic applications and provide improved safety and/or comfort to the users.
Pharmaceutical formulations are commonly provided in multi-use bottles. Formulations, such as ophthalmic compositions, find uses in many ophthalmic applications. These compositions are often instilled directly into the eye one or more times a day to either deliver medications or to relieve symptoms of eye conditions, such as dry eye or inflammation of the superficial tissues of the eye accompanying various allergic reactions (such as hay fever allergies and the like, irritation of the eye due to foreign bodies, or eye fatigue). Other ophthalmic solutions are employed in the field of contact-lens care. Contact-lens solutions are utilized to soak, disinfect, clean, and wet contact lenses. These solutions are not instilled directly in the eye from the bottle, but do subsequently come into contact with the eye when the lenses are placed on the eye.
Ophthalmic compositions are provided sterile, but once opened, are susceptible to microbial contamination. In the case of multi-use solutions, the formulations contain at least a preservative designed to kill microorganisms that come in contact with the solution, protecting the patient from infection due to a contaminated ophthalmic solution during the prescribed usage.
Typically, preservatives for ophthalmic compositions fall into two traditional categories: alcohols and amines or ammonium-containing compounds. Typical alcohol-based anti-microbial agents include benzyl alcohol, phenethyl alcohol, and chlorbutanol. Alcohol-based preservatives work by disorganizing the lipid structure of cell membrane, and thus increase permeability of the cell wall, leading to cell lysis. These alcohols have limited solubility in aqueous solutions and tend not to be stable preservatives due to being susceptible to oxidation, evaporation, and interaction with the plastic bottle. More commonly, organic amines and ammonium-containing compounds are utilized as anti-microbial agents in ophthalmic solutions. Representative compounds in this category include benzalkonium chloride (“BAK”), benzododecinium bromide (“BDD”), chlorhexidine, polymeric biguanide (such as polyhexamethylene biguanide or “PHMB”). It is believed that the electrophilicity of the nitrogen-containing moieties of these compounds promotes their interaction with the negatively charged cell membranes of the microorganisms, leading to cell lysis, and thus severely impacting their survival.
Although amines and ammonium-containing compounds have good anti-microbial activity, and are used commercially to preserve ophthalmic solutions, there are significant disadvantages associated with these compounds. In particular, these compounds used at higher doses can be toxic to the sensitive tissues of the eye. For example, BAK-containing ophthalmic solutions are known to cause eye irritation in patients. It causes growth arrest at very low concentration (0.00001%), apoptosis at 0.01%, and necrosis at higher concentrations (0.05-0.1%). Patients who may be at greater risk of BAK-induced adverse effects are those with dry-eye syndrome since they often need to use eye drop over an extended period of time. Polymeric amines and ammonium-containing compounds are less toxic than BAK but still can cause irritation responses in some other patients. For example, polyquaternium-1 (α-4-{tris(2hydroxyethyl)ammonium-2-butenyl} poly {1-dimethylammonium-2-butenyl}-ω-tris(2-hydroxyethyl)ammonium chloride), also known as Polyquad®, has been shown to be less toxic than BAK and used in a limited number of ophthalmic formulations. However, polyquaternium-1 still shows some adverse effects on ocular tissues. A 0.5% polyquaternium-1 formulation has been shown significantly to decrease goblet cell density. Healthy goblet cells are required to produce adequate mucin, which is one of three component layers of the tear film. A. Labbé et al., J. Ocular Pharmacol. & Therapeutics, Vol. 22, No. 4, 267 (2006). Chlorhexidine, on the other hand, has proven to be more biocompatible than the other amines and ammonium-containing anti-microbial agents and, therefore, non-irritating at the levels typically used. However, the mildness of chlorhexidine to the ocular environment is offset by the fact that chlorhexidine is a relatively weak preservative.
Oxidative preservatives, which work by oxidizing cell walls or membranes, affecting membrane-bound enzymes, and disrupting cellular function. U.S. Pat. Nos. 5,576,028; 5,607,698; 5,725,887; and 5,807,585 and European Patent 035486 disclose solutions, which may be ophthalmic solutions or contact lens solutions, containing from 10 ppm (0.001%) to 1000 ppm (0.1%) hydrogen peroxide and a hydrogen peroxide stabilizer. However, the long-term preservative efficacy of these solutions is not known. It is suggested in these patents that hydrogen peroxide concentration should be in trace amounts in order to be tolerable to the patient upon direct application. At trace concentrations, stabilizers are needed to prevent decomposition of hydrogen peroxide.
On the other hand, various polysaccharides have been used as viscosity modifiers or drug delivery agents in pharmaceutical compositions. For example, the use of alginate as a thickener for topical ophthalmic use is disclosed in U.S. Pat. No. 6,528,465 and U.S. Patent Application Publication 2003/0232089. U.S. Pat. No. 5,776,445 discloses the use of alginate as a drug delivery agent that is topically applied to the eye. U.S. Patent Application Publication 2003/0232089 teaches a dry-eye formulation that contains two polymer ingredients including alginate.
However, polysaccharides are not normally compatible with oxidative agents in pharmaceutical compositions. Thus, the preparation of useful compositions comprising polysaccharides and oxidative preservatives presents a significant technical challenge to people in the field.
Therefore, there is a continued need to provide improved pharmaceutical formulations that comprise a polysaccharide and an effective preservative that provides improved safety and/or comfort to the users. It is also very desirable to provide improved ophthalmic solutions having such advantages.